Cancer is projected to become the leading cause of death worldwide by 2010. The global burden of cancer doubled between 1975 and 2000. By 2020, it is projected to double again, and to triple by 2030. Multiple myeloma (MM) is a particularly deadly type of cancer. In 2008, 19,920 Americans were diagnosed with MM, and 10,690 died. Five-year survival rates are only 32%. Treatments vary, but generally include chemotherapy, and occasionally radiation therapy. More recently, immunotherapies have also been developed with some valuable, albeit limited, successes. The goal of this work is to advance the development of a novel cell-based immunotherapy into the clinic by completing toxicology testing and identification of key biomarkers in a murine MM model. After completion of the proposed work, we will begin a clinical trial in humans. Longer term, and based on our substantial preclinical data, we will expand the clinical application of this therapy to other cancers, both liquid and solid. In our therapy, T cells are modified to express chimeric NKG2D (chNKG2D) receptors, expanded, and then returned to the patient (for MM, typically intravenously). The receptor was designed to combine key features of two immune cell types: the ligand specificity of NKG2D receptor and the signaling domain of CD3zeta together create a receptor which enables T cells to recognize and kill tumor cells while significantly altering the tumor microenvironment. Because the NKG2D receptor is absent or expressed at very low levels in normal tissues, specificity is outstanding. Further, the therapy activates host immunity against other tumor antigens, which broadens targeting and will make it less likely for tumor variants to emerge. Finally, the modified T cells are eliminated from the host, but the induced immune response is durable and protects against future tumor challenge, even in the absence of the modified T cells. Immunotherapy with chNKG2D-bearing T cells leverages the power of the immune system by combining the best features of NK and T cells. This approach is particularly compelling as it is not limited to MM. In fact, 70% of all cancers may express the ligands for this receptor. We have equally exciting in vivo data in murine lymphoma and ovarian cancer models making MM - while unquestionably a disease well worth our attention - a model indication. We will complete preclinical toxicology, including determination of Maximum Tolerated Dose (MTD) for single and multiple administrations using the chimeric receptor, wild type receptor, and HBSS as a control, in both tumor-bearing and tumor-free mice (Aim I). In-depth pathology and histology will allow us to identify biomarkers which will be essential for clinicians during clinical trials (Aim II). PUBLIC HEALTH RELEVANCE: By 2010, cancer is projected to be the leading killer worldwide. By removing, purifying, modifying, growing, then infusing a patient's immune cells, we have been able to target and kill both liquid and solid cancers, and to simultaneously train the patient's own immune system to do likewise (e.g. to prevent metastatic disease). This project will complete the toxicology studies in mice that are required before we begin a clinical trial in humans.